Frontline Axi-Cel Achieves High Response Rate in High-Risk LBCL

Sattva S. Neelapu, MD

With first-line axicabtagene ciloleucel (axi-cel; Yescarta), a high rate of rapid and durable responses were observed in patients with high-risk large B-cell lymphoma (LBCL), according to updated results from the ZUMA-12 study (NCT03761056).

In 37 evaluable patients, the objective response rate (ORR) in the study was 89% (95% CI, 75%-97%) with complete responses (CRs) in 78%. Partial responses (PRs) were observed in 11% of the evaluable population, while 8% has stable disease (SD), and only 3 had progressive disease (PD).

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that already has FDA approval for the treatment of adults with relapsed or refractory LBCL and relapsed/refractory follicular lymphoma following at least 2 prior lines of therapy. ZUMA-12 is the first study to assess treatment with axi-cel in the first-line setting.

“Patients with high-risk large B cell lymphoma have poor outcomes, including lower response rates and poor overall survival. In addition, patients with early disease resistance as assessed by dynamic PET scan, after first-line chemoimmunotherapy have an increased risk of death,” said Sattva Neelapu, MD, professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, and deputy department chair, Department of Lymphoma/Myeloma, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX during a presentation at the 2022 Transplantation and Cellular Therapy Meetings.

Based on the unmet medical need for therapies to improve outcomes in high-risk LBCL, ZUMA-12 was created. The study is a phase 2, multicenter, open-label, single-arm study. At the 2022 TCT Meetings, Neepalu presented results on efficacy, safety, pharmacokinetics, and pharmacodynamics.

Per the study design, patients included in ZUMA-12 were those with high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 translocations or have an International Prognostic Index (IPI) score of ≥ 3. All patients must be 18 years of age or older with an ECOG performance score of 0 or 1, and their interim PET scan should show a Deauville score of 4 or 5 after 2 cycles of anti-CD20 mAb plus an anthracycline-containing regimen.

“Following enrollment and leukapheresis, patients could receive optional non-chemotherapy bridging, which could have included either corticosteroids or localized radiation. And once the product has been generated, they received standard [fludarabine] conditioning followed by a single infusion of axi-cel,” explained Neelapu about ZUMA-12 treatment.

The fludarabine conditioning was administered at 30 mg/m2 via intravenous (IV) infusion with cyclophosphamide 500 mg/m2 IV on days -5, -4, and -3. Axi-cel was administered at 2 x 106 CAR T cells/kg on day 0.

The primary end point of the ZUMA-12 study is CR rate assessed by investigators per Lugano 2014 classification. Secondary end points of the study include ORR, duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), safety, and CAR T cells in blood and cytokine levels in serum.

Of the 42 patients enrolled, 40 were treated with condition chemotherapy and axi-cel. The patients had a median age of 61 years (range, 23-86), and were 68% male. In terms of disease characteristics, 95% of patients in the study has stage III or IV disease, 63% had an ECOG score of 1, and 100% had at least 1 prior systemic therapy. FISH testing assessed by investigator showed that 40% of patients had double- or triple-hit, and 25% were double- or triple-hit per central laboratory assessment. Also, the IPI score was ≥ 3 for 78% of patients, and 48% had a Deauville score of 4, while 53% had a Deauville score of 5.

The median follow-up for response in the evaluable population was 15.9 months (range, 6.0-26.7), with 62% of patients having been followed for ≥ 12 months. As of the data cutoff date, 73% of patients were having an ongoing response to axi-cel. The median time to response was 1.0-month (range, 0.9-6.8). Of the 11% who initially had a PR, 16% eventually converted to a PR. Moreover, 3% of those whose initial response was SD converted to a CR.

In the overall population (n = 40), the ORR was 90% (95% CI, 76%-97%) with a CR rate of 80% (95% CI, 64%-91%. Notably, CRs were consistent across all subgroup populations. The median DOR was not reached, but at month 12, the DOR rate was 80.8% (95% CI, 59.3%-91.6%).

All survival outcomes had not been reached by the time of data cut off. At 12 months, the EFS rate was 72.5% (95% CI, 53.1%-84.9), the PFS rate was 74.6% (95% CI, 54.8%-86.7%, and the OS rate was 90.6% (95% CI, 73.4%-96.9%).

Any-grade treatment-emergent adverse events (TEAEs) occurred in all 40 patients in the study of which, 85% were grade 3 or higher. The most common grade ≥ 3 axi-cel-related TEAEs were neutrophil count decrease (53%), white blood cell count decrease (43%), anemia (30%), encephalopathy (15%), and platelet count decrease (15%).

Serious TEAEs were observed in 45% of patients. In 68% of patients, grade ≥ 3 cytopenias occurred, and 15% experienced grade ≥ 3 infections. Twelve of patients died due to either PD (10%), COVID-19 (3%), or septic shock (3%).

Cytokine release syndrome (CRS) occurred in all patients in the study, but only 8% experienced grade 3 CRS. The most common CRS-related symptoms observed were pyrexia (100%), hypotension (30%), chills (25%), and hypoxia (23%).

“Tocilizumab was administered in 63% of outpatients and corticosteroids in 35% of the patients for management of CRS, only one patient required vasopressors,” noted Neelapu. “The median time to onset of CRS was four days and the median duration was 6 days. There were no grade 4 grade 5 CRS events and all CRS events resolved as of the data cut off.”

Neurologic events of any grade were observed in 73% of patients, and these events were grade 3 for 23% and grade 2 for 38%. The most common symptoms associated with neurologic events in the study were confusional state (28%), encephalopathy (25%), and tremor (25%).

Regarding neurologic events, Neelapu stated: “The median time to onset was 9 days and the median duration was 7 days. There were 2 grade 4 neurological events both due to encephalopathy and both resolved. There were no grade 5 neurological events noted. As of the data cut off, there's 1 patient who has an ongoing grade 1 tremor.”

Finally, ZUMA-12 results were compared with results from ZUMA-1 (NCT02348216), in which axi-cel was evaluated as third-line treatment for patients with LBCL.

“We observed a higher frequency of CCR7-positive, CD45RA-positive T cells in ZUMA-12 versus in ZUMA-1. Within the product, 35% of these T cells were of this phenotype on ZUMA-12 versus only 14% on ZUMA-1. And this was a phenotype that was previously associated with a favorable newer PK profile and better clinical efficacy,” said Neelapu.

The greater frequency of CCR7-positive, CD45RA-positive T cells observed in ZUMA-12 was associated with greater CAR T-cell expansion, which signals improved T-cell fitness in the first-line setting. Based on the collective findings, Neelapu et al., axi-cel may be beneficial to patients exposed to fewer prior therapies as well as those with high-risk LBCL.

_REFERENCES:

_{Neelapu SS, Dickinson M, Munoz JL, et al. Primary analysis (PA) of Zuma-12: A phase 2 study of axicabtagene ciloleucel (Axi-Cel) as first-line therapy in patients (Pts) with high-risk large b-cell lymphoma (lbcl). Presented at. 2022 Transplantation and Cellular Therapy Meetings; April 23-26, 2022; Salt Lake City, UT. Abstract 12.}